Immunodeficiency typically manifests as recurrent infections. However, more likely causes of recurrent infections in children are repeated exposures to infection at day care or school (infants and children may normally have up to 10 respiratory infections/yr), and more likely causes in children and adults are inadequate duration of antibiotic treatment, resistant organisms, and other disorders that predispose to infection (eg, congenital heart defects, allergic rhinitis, ureteral or urethral stenosis, immotile cilia syndrome, asthma, cystic fibrosis, severe dermatitis).

Immunodeficiency should be suspected when recurrent infections are the following:

Severe

Complicated

In multiple locations

Resistant to treatment

Caused by unusual organisms

Present in family members

Initially, infections due to immunodeficiency are typically upper and lower respiratory tract infections (eg, sinusitis, bronchitis, pneumonia) and gastroenteritis, but they may be serious bacterial infections (eg, meningitis, sepsis).

Immunodeficiency should also be suspected in infants or young children with chronic diarrhea and failure to thrive, especially when the diarrhea is caused by unusual viruses (eg, adenovirus) or fungi (eg,
Cryptosporidium sp). Other signs include skin lesions (eg, eczema, warts, abscesses, pyoderma, alopecia), oral or esophageal thrush, oral ulcers, and periodontitis.

Less common manifestations include severe viral infection with herpes simplex or varicella zoster virus and CNS problems (eg, chronic encephalitis, delayed development, seizure disorder). Frequent use of antibiotics may mask many of the common symptoms and signs. Immunodeficiency should be considered particularly in patients with infections and an autoimmune disorder (eg, hemolytic anemia, thrombocytopenia).

Evaluation

History and physical examination are helpful but must be supplemented by immune function testing. Prenatal testing is available for many disorders and is indicated if there is a family history of immunodeficiency and the mutation has been identified in family members.

History

Clinicians should determine whether patients have risk factors for infection or a history of symptoms of secondary immunodeficiency disorders and/or risk factors for them. Family history is very important.

Age when recurrent infections began is important.

Onset before age 6 mo suggests a T-cell defect because maternal antibodies are usually protective for the first 6 to 9 mo.

Onset between the age of 6 and 12 mo may suggest combined B- and T-cell defects or a B-cell defect, which becomes evident when maternal antibodies are disappearing (at about age 6 mo).

Onset much later than 12 mo usually suggests a B-cell defect or secondary immunodeficiency.

In general, the earlier the age at onset in children, the more severe the immunodeficiency. Often, certain other primary immunodeficiencies (eg, common variable immunodeficiency [CVID]) do not manifest until adulthood.

If results are normal, immunodeficiency (especially Ig deficiency) can be excluded. If results are abnormal, further tests in specialized laboratories are needed to identify specific deficiencies. If chronic infections are objectively documented, initial and specific tests may be done simultaneously. If clinicians suspect that immunodeficiency may be still developing, tests may need to be repeated, with monitoring over time, before a definitive diagnosis is made.

CBC can detect abnormalities in one or more cell types (eg, WBCs, platelets) characteristic of specific disorders, as in the following:

Neutropenia (absolute neutrophil count < 1200 cells/μL) may be congenital or cyclic or may occur in aplastic anemia.

Lymphopenia (lymphocytes < 2000/μL at birth, < 4500/μL at age 9 mo, or < 1000/μL in older children or adults) suggests a T-cell disorder because 70% of circulating lymphocytes are T cells.

Quantitative serum Ig levels are measured. Low serum levels of IgG, IgM, or IgA suggest antibody deficiency, but results must be compared with those of age-matched controls. An IgG level < 200 mg/dL usually indicates significant antibody deficiency, although such levels may occur in protein-losing enteropathies or nephrotic syndrome.

IgM antibodies can be assessed by measuring isohemagglutinin titers (anti-A, anti-B). All patients except infants < 6 mo and people with blood type AB have natural antibodies at a titer of ≥ 1:8 (anti-A) or ≥ 1:4 (anti-B). Antibodies to blood groups A and B and to some bacterial polysaccharides are selectively deficient in certain disorders (eg, Wiskott-Aldrich syndrome, complete IgG2 deficiency).

With
skin testing, most immunocompetent adults, infants, and children react to 0.1 mL of
Candida albicans extract (1:100 for infants and 1:1000 for older children and adults) injected intradermally. Positive reactivity, defined as erythema and induration > 5 mm at 24, 48, and 72 h, excludes a T-cell disorder. Lack of response does not confirm immunodeficiency in patients with no previous exposure to
Candida.

Chest x-ray may be useful in some infants; an absent thymic shadow suggests a T-cell disorder, especially if the x-ray is obtained before onset of infection or other stresses that may shrink the thymus. Lateral pharyngeal x-ray may show absence of adenoidal tissue.

Additional testing

If clinical findings or initial tests suggest a specific disorder of immune cell or complement function, other tests are indicated.

If patients have recurrent infections and lymphopenia, lymphocyte phenotyping using flow cytometry and monoclonal antibodies to T, B, and natural killer (NK) cells is indicated to check for lymphocyte deficiency.

If cellular immunity deficiency is suspected, the T-cell receptor excision circle (TREC) test can be done to identify infants with low T-cell counts. If tests show that T cells are low in number or absent, in vitro mitogen stimulation studies are done to assess T-cell function. If MHC antigen deficiency is suspected, serologic (not molecular) HLA typing is indicated. Some experts recommend screening all neonates with a TREC test; testing is done routinely in some US states.

If humoral immunity deficiency is suspected, patients may be tested for specific mutations—for example, in the genes that encode for Bruton tyrosine kinase (BTK), CD40 and CD40 ligand, and nuclear factor-kappa-B essential modulator (NEMO). A sweat test is typically done during the evaluation to rule out cystic fibrosis.

If combined cellular and humoral immunity is impaired and SCID is suspected, patients can be tested for certain typical mutations (eg, in the IL-2 receptor gamma [
IL-2RG
, or
IL-2Rγ
] gene).

If phagocytic cell defects are suspected, CD15 and CD18 are measured by flow cytometry and neutrophil chemotaxis is tested. A flow cytometric oxidative (respiratory) burst assay (measured by dihydrorhodamine 123 [DHR] or nitroblue tetrazolium [NBT]) can detect whether O2radicals are produced during phagocytosis; no production is characteristic of chronic granulomatous disease.

If the type or pattern of infections suggests complement deficiency, the serum dilution required to lyse 50% of antibody-coated RBCs is measured. This test (called CH50) detects complement component deficiencies in the classical complement pathway but does not indicate which component is abnormal. A similar test (AH50) can be done to detect complement deficiencies in the alternative pathway.

Prenatal and neonatal diagnosis

An increasing number of primary immunodeficiency disorders can be diagnosed prenatally using chorionic villus sampling, cultured amniotic cells, or fetal blood sampling, but these tests are used only when a mutation in family members has already been identified.

X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, ataxia-telangiectasia, X-linked lymphoproliferative syndrome, all forms of SCID (using the TREC test), and all forms of chronic granulomatous disease can be detected.

Sex determination by ultrasonography can be used to exclude X-linked disorders.

Prognosis

Prognosis depends on the primary immunodeficiency disorder.

Most patients with an Ig or a complement deficiency have a good prognosis with a near-normal life expectancy if they are diagnosed early, are treated appropriately, and have no coexisting chronic disorders (eg, pulmonary disorders such as bronchiectasis).

Other immunodeficient patients (eg, those with a phagocytic cell defect or combined immunodeficiencies, such as Wiskott-Aldrich syndrome or ataxia-telangiectasia) have a guarded prognosis; most require intensive and frequent treatment.

Some immunodeficient patients (eg, those with SCID) die during infancy unless immunity is provided through transplantation. All forms of SCID could be diagnosed at birth if a WBC count and manual differential of cord or peripheral blood were routinely done in neonates. Suspicion for SCID, a true pediatric emergency, must be high because prompt diagnosis is essential for survival. If SCID is diagnosed before patients reach age 3 mo, transplantation of stem cells from a matched or half-matched (haploidentical) relative is lifesaving in 95%.

Pearls & Pitfalls

To prevent early death, strongly consider screening all neonates for SCID using a T-cell receptor excision circle (TREC) test.

Patients at risk of serious infections (eg, those with SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome, or asplenia) or of specific infections (eg, with
Pneumocystis jirovecii in patients with T-cell disorders) can be given prophylactic antibiotics (eg, 5 mg/kg trimethoprim/sulfamethoxazole po bid).

To prevent graft-vs-host disease after transfusions, clinicians should use blood products from cytomegalovirus-negative donors; the products should be filtered to remove WBCs and irradiated (15 to 30 Gy).

Management of acute infection

After appropriate cultures are obtained, antibiotics that target likely causes should be given promptly. Sometimes surgery (eg, to drain abscesses) is needed.

Replacement of missing immune components

Such replacement helps prevent infection. Therapies used in more than one primary immunodeficiency disorder include the following:

IV immune globulin (IVIG) is effective replacement therapy in most forms of antibody deficiency. The usual dose is 400 mg/kg once/mo; treatment is begun at a low infusion rate. Some patients need higher or more frequent doses. IVIG 800 mg/kg once/mo helps some antibody-deficient patients who do not respond well to conventional doses, particularly those with a chronic lung disorder. High-dose IVIG aims to keep IgG trough levels in the normal range (> 600 mg/dL).

Subcutaneous immune globulin (SCIG) can be given instead of IVIG. SCIG can be given at home, usually by patients themselves. The usual dose is 100 to 150 mg/kg once/wk. Because SCIG and IVIG differ in bioavailability, the dose of SCIG may need to be adjusted if patients are switched from IVIG. With SCIG, local site reactions are a risk, but SCIG seems to have fewer systemic adverse effects.

Hematopoietic stem cell transplantation using bone marrow, cord blood, or adult peripheral blood stem cells is effective for lethal T-cell and other immunodeficiencies. Pretransplantation chemotherapy is unnecessary in patients without T cells (eg, those with SCID). However, patients with intact T-cell function or partial T-cell deficiencies (eg, Wiskott-Aldrich syndrome, combined immunodeficiency with inadequate but not absent T-cell function) require pretransplantation chemotherapy to ensure graft acceptance. When a matched sibling donor is unavailable, haploidentical bone marrow from a parent can be used. In such cases, mature T cells that cause graft-vs-host disease must be rigorously depleted from parental marrow before it is given. Umbilical cord blood from an HLA-matched sibling can also be used as a source of stem cells. In some cases, bone marrow or umbilical cord blood from a matched unrelated donor can be used, but after transplantation, immunosuppressants are required to prevent graft-vs-host disease, and their use delays restoration of immunity.

Retroviral vector gene therapy has been successful in a few patients with X-linked and ADA-deficient SCID, but this treatment is not widely used because some patients with X-linked SCID developed leukemia.

Key Points

Consider a primary immunodeficiency if infections are unusually frequent or severe, particularly if they occur in family members, or if patients have thrush, oral ulcers, periodontitis, or certain skin lesions.

Do a complete physical examination, including the skin, all mucous membranes, lymph nodes, spleen, and rectum.

MSD and the MSD Manuals

Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside of the US and Canada) is a global healthcare leader working to help the world be well. From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world. The Manual was first published in 1899 as a service to the community. The legacy of this great resource continues as the Merck Manual in the US and Canada and the MSD Manual outside of North America. Learn more about our commitment to Global Medical Knowledge.